Project Summary Metabolic syndrome has become a major public challenge in modern society. One main cause is an imbalance between energy uptake and expenditure, which is actively modulated by environmental factors such as diet composition, circadian rhythms of feeding and sleeping, and the intestinal microbiota. The gut microbiota is a vast community of microorganisms that colonize the intestine, and it plays an essential role in mammalian me- tabolism by liberating absorbable nutrients from complex diets for host uptake. Interestingly, recent studies have shown that the microbiota can also impact host metabolic activities by regulating the circadian clock, and disrupting this crosstalk can cause metabolic disorders. Despite this general understanding, the underlying mechanisms remain elusive. My preliminary studies have revealed that circadian oscillation of histone acetyla- tion in intestinal epithelial cells depends on the microbiota. Furthermore, I have identified a potential mecha- nism involving microbial activation of histone deacetylase 3 (HDAC3) expression. I found that many genes en- coding nutrient uptake and metabolic functions are targeted by the cycling histone acetylation signals. Epitheli- al cell-specific HDAC3-deficient mice exhibit a complete loss of histone acetylation oscillation and disrupted rhythms of blood glucose levels. The mutant mice take up less lipid and are resistant to high fat diet-induced obesity. Dissecting the microbial-epithelial signaling circuits reveals that specific components of the gut micro- biota and immune system activate epithelial HDAC3. For these reasons, I hypothesize that the gut microbiota drives the circadian rhythms of transcription and nutrient uptake by activating intestinal epithelial HDAC3, which in turn helps to maintain energy homeostasis and metabolic health. In Aim 1, I will study the mecha- nisms by which the microbiota regulates the rhythms of intestinal gene expression and nutrient absorption. In Aim 2, I will determine how the gut microbiota regulates lipid uptake and energy homeostasis through epithelial HDAC3 and its downstream targets. In Aim 3, I will combine immunological, proteomic and computational ap- proaches to identify the mechanisms by which the microbiota activates epithelial HDAC3, identify co-factors of HDAC3, and determine their metabolic functions. These studies will provide novel insights into how the micro- biota regulates host circadian and metabolic states and will help develop new strategies to protect against metabolic diseases by targeting HDACs or the microbiota.